December 2007 Vol 8 After Meeting.indd ABSTRACT Nodular lymphocyte predominant Hodgkin’s lymphoma (NLPHL) is a recently described type of Hodgkin’s lymphoma (HL) and accounts for 5-6% of all the cases of HL. Here we report the case of an elderly man who presented to Sultan Qaboos Uni- versity Hospital, Oman, with severe hypercalcemia, and was diagnosed to have stage IV NLPHL. Although the incidence of hyper- calcemia is estimated to be between -5% in classical HL, to our knowledge this is the first report of NLPHL presenting with severe hypercalcemia. The patient responded to the anti-CD20 monoclonal antibody, Rituximab, and has been in clinical remission for more than 3 years. Keywords: Hodgkin’s Lymphoma; Hypercalcemia; Thrombocytopenia; Monoclonal antibody; Rituximab; Case Report; Oman N0dular Lymphocyte Predominant Hodgkin’s Lymphoma Presenting as Severe Hypercalcaemia: A Case Report *Ikram A Burney,1 V Nirmala,2 Mansour S Al-Moundhri,1 Nicholas J Woodhouse1 1Department of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, P. O. Box 35, Al-Khod 123, Sultanate of Oman; 2Department of Pathalogy, College of Medicine and Health Sciences, Sultan Qaboos University, P. O. Box 35, Al-Khod 123, Sultanate of Oman *To whom correspondence should be addressed. Email: ikram@squ.edu.om شديد كفرط املعروض السائدة اللمفاوية العقد ذي هودجكن ملفومة حالة تقرير الدم: كالسيوم في وودهاوز ، نيكوالس ، منصور املندري ،في نرماال برني اكرام ملفومة كل حاالت وتشكل5-%6 من ، وصفت حديثا التي هودجكن ملفومة أنواع احدى هي السائدة العقد اللمفاوية ذي امللخص: ملفومة هودجكن ، وكان بالدم مستوى الكالسيوم في شديد ولديه فرط (عمان) قابوس جامعة السلطان ــفى مستش راجع ــن الس رجل كبير حالة نورد هنا هودجكن. بالدم ــيوم الكالس ــتوى مس فرط حصول معدل ولو أن ، ــائدة العقد اللمفاوية الس ذي هودجكن من ملفومة الرابعة املرحلة في مرضه انه ــخيص تش يعرض الذي السائدة اللمفاوية ذي العقد هودجكن للمفومة تقرير أول هذا يكون وحسب علمنا ، الكالسيكية ملفومة هودجكن 1-%5 في بني يتراوح من خاليا وكان ، (ريتوكسيماب) النسيلة احادية املضادة االجسام CD20 من املريض ملضاد استجاب في الدم. الكالسيوم مستوى في طبيا كفرط سنوات. ملدة ثالث سريرية) أَة دْ (هَ االعراض عمان. حالة، تقرير ريتوكسيماب، ، النسيلة احادية مضادة أجسام عالج ، ، يحات فَ الصُّ قِلَّةُ ، الدم في الكالسيوم فرط هودجكن ، الكلمات: ملفومة مفتاح SULTAN QABOOS UNIVERSITY MEDICAL JOURNAL DECEMBER 2007 VOL 7, NO. 3, P. 247-251 SULTAN QABOOS UNIVERSITY© SUBMITTED - 15TH APRIL 2007 ACCEPTED - 1ST SEPTEMBER 2007 C A S E R E P O R T A 75 YEAR OLD OMANI GENTLEMAN, presented with a 6 month history of weak-ness, weight loss of 20 kg, loss of appetite and a two month history of low grade fever, cough and difficulty in walking. The past medical history was significant for hypertension for 20 years (treated with atenolol), Type II diabetes mellitus (treated with oral hypoglycemics), chronic renal failure for 8 years; hypertrophic cardiomyopathy diagnosed 2 years previ- ously; and osteoarthritis with a right knee joint replace- ment. General physical examination was unremarkable except for generalized body weakness and an ejection systolic murmur suggestive of aortic sclerosis. Laboratory investigations revealed: Hb 13g/dl, WBC 6.5 x 109/L, platelets 66 x 109/L; creatinine 313 µmol/L; Na+ 132 mmol/L; K+ 3.8 mmol/L; Cl 100 mmol/L; CO2 19 mmol/L; corrected serum calcium 4.08 mmol/L; PO4 1.88 mmol/L; alkaline phophatase 94 U/L. Serum para-thyroid hormone (PTH) levels were appropriately reduces to 0.7 pmol/L (1.3-7.6 pmol/L), whereas, serum para-thyroid hormone related peptide (PTH-rp) < 1.0 pmol/L (<1.3 pmol/L); was within the normal limits; however, 1,25 dihydroxyvitamin D3 [1,25 (OH) D3] was elevated at 411 pmol/L (43-148 pmol/L). An assessment of thyrombocytopenia, renal failure and severe hypercalcemia secondary to elevated 1,25 (OH) D3 was made. An upper GI endoscopy revealed severe hemor- I K R A M A B U R N E Y, V N I R M A L A , M A N S O U R S A L - M O U N D H R I A N D N I C H O L A S J WO O D H O U S E 248 rhagic gastritis and reflux esophagitis. The parathy- roid scan was reported normal. A CT (computed to- mography) scan of the chest and abdomen revealed a left axillary lymph node measuring 4x2 cm, which was not palpable on clinical examination. A core biopsy of the lymph node was done which revealed an infiltrate consisting of occasional atypi- cal large cells (positive for CD20, CD79a, and CD45, weakly positive in a few cells for CD30, and negative for CD5, CD10, CD15, bcl-1, and epithelial membrane antigen). These large atypical cells were interspersed within a background of small lymphocytes (positive for CD3 and CD5), some of which were arranged in a rosette fashion (positive for CD57) around the CD20 positive large atypical lymphocytes. Overall, the his- topathological picture was suggestive of either a lym- phocyte predominant Hodgkin’s lymphoma (NLPHL) or a T-cell/histiocyte rich B-cell lymphoma (T/HRB- CL). The bone marrow biopsy showed increased cellu- larity and scattered large atypical lymphocytes, stain- ing positively for the CD20 antigen. The patient was diagnosed to have NLPHL/ T/HR- BCL, stage IV. Although the histopathology was more in favor of NLPHL, the clinical presentation (age and stage IV disease) was more in keeping with T/HRBCL. A second opinion, sought from a reference pathology centre (Armed Forces Institute of Pathology, Wash- ington, USA), was consistent with the original impres- sion of NLPHL. However, in view of the CD57 posi- tive small lymphocytes arranged in a rosetting manner around the large malignant cells, a diagnosis of NL- PHL was favoured. The patient was treated with zolendronic acid re- sulting in normalization of elevated calcium levels in the next 48 hours. Subsequently, the patient was treat- ed with anti-CD20 antibody (Rituximab) weekly for 4 weeks. Platelet count improved and reached normal limits during the course of treatment with Rituximab. The 1,25 (OH) D3 returned to 45 pmol/L in 2 weeks. Re-evaluation CT scans at 2 months revealed a partial remission (PR) and at 6 months revealed complete re- mission (CR). A bone marrow biopsy 2 months later was reported to be within the normal limits. D I S C U S S I O N NLPHL is a rare type of B-cell lymphoma with unique pathologic and clinical features that distinguish it from classical Hodgkin’s lymphoma.1-3 Patients with NLPHL tend to be younger males who present with indolent and asymptomatic lymphadenopathy limited to peripheral lymph nodes. The immunophenotype of the malignant lymphocytic and/or histiocytic cells forms the basis of the pathologic distinction from the subtypes of classical Hodgkin’s disease.1 Despite an ex- cellent response to an initial combined-modality treat- ment, patients with NLPHL tend to relapse.2 The be- nign nature of these relapses and the incidence of late treatment-related toxicity have raised questions about the need for an aggressive upfront approach. However, recent insights into the molecular pathogenesis of NL- PHL and the development of novel targeted therapies promise to improve future treatment.3 Although, in our case, a diagnosis of NLPHL was entertained, T/HRBCL was a close differential. NL- PHL and T/HRBCL are distinct tumors and are treat- ed differently. They are linked by a morphologic and Figures 1: Photomicrographs of section from the lymph node. (1A) H&E stain. Arrows indicate the atypi- cal cells. (1B) Staining with CD20 antibody. Arrow indicates the membrane staining of the large atypical cell. (1C) Staining with CD57 antibody. Arrows indicate the small lymphocytes arranged in a rosette fashion around the large atypical cells N 0 D U L A R LY M P H O C Y T E P R E D O M I N A N T H O D G K I N ’ S LY M P H O M A P R E S E N T I N G A S S E V E R E H Y P E R C A L C E M I A 249 probably a biologic continuum, which renders the dif- ferential diagnosis difficult.4, 5 The NLPHL is charac- terized by atypical lymphocytic and histiocytic (L&H) or ‘popcorn’ cells, embedded in the background of progressively transformed follicles. The atypical cells are CD45+, express the B-cell associated antigens CD19, CD20, CD22, CD79a, and epithelial membrane antigen (EMA), but lack the expression of CD15 and CD30.6 While tumor cells in NLPHL and T/HRBCL are immunophenotypically similar, the background composition differs. In NLPHL, small B cells are CD3+ CD4+ CD57+ T cells, whereas in T/HRBCL, CD8+ T cells and histiocytes dominate. While CD57+ T cells surrounding the ‘popcorn cells’ are typically seen in NLPHL, the absence of these cells in the rosettes form does not argue against the diagnosis.3 Tumor cells ei- ther are loosely scattered or formed clusters, thus re- sembling areas of either T/HRBCL or inflammatory diffuse large BCL (DLBCL) within the nodules.5 On the other hand, diffuse large B cell lymphoma (DLBCL) can arise in patients previously known to have, or have been treated for NLPHL. For example, the Nebraska group has reported 21 patients in whom DLBCL was diagnosed either concurrently or subse- quent to a diagnosis of NLPHL.7 Of the ten patients who presented with nodal DLBCL only, six patients presented with both nodal and extra-nodal involve- ment, and five presented with only extra-nodal DL- BCL. The median overall survival and failure-free survival of the entire group was 35 months and 11 months. Importantly, there were no significant differ- ences in the survival outcomes between patients with DLBCL arising in NLPHL and age-and sex-matched patients with de novo DLBCL. Our patient remained progression-free after 6 months of treatment, and is on regular follow up. The vast majority of patients with NLPHL present with stage I/II disease and bone marrow involvement is rare.2, 3 However, a small subset of patients in whom lymph node biopsy shows NLPHL with a nodular pat- tern also may have lymphoma in the bone marrow. Khoury et al. reported the incidence of bone marrow involvement to be 2.5% in a series of 275 patients with classical HL.8 Bone marrow involvement is associated with laboratory, radiological, or morphologic evidence of aggressive disease, and our patient did present with severe hypercalcemia. Hypercalcemia is not a common feature of Hodg- kin’s lymphoma.9, 10 The incidence has been reported to be 0.9%, 1.6%, and 5.4% in different series of patients with classical HL.11 However, little information exists on hypercalcemia in patients with NLPHL. Hodgkin’s lymphoma associated hypercalcemia, although un- common, has been variously ascribed to be mediated through the secretion of PTH-rp, osteoclast activat- ing factors (OAFs), overproduction of 1,25 (OH) D3 (calcitriol), or due to prostaglandin synthesis.12-15 In our case, serum PTH and PTH-rp levels were either suppressed or within the normal limits. However, se- rum 1,25 (OH) D3 levels were found to be elevated. Calcitriol has been most consistently implicated as the mediator of hypercalcemia in HL.16 Monocytes and macrophages seem to play a pivotal role in the pro- duction of calcitriol in HL and NHL, as is the case in tuberculosis and sarcoidosis. Calcitriol synthesis by macrophages is enhanced by interferon-γ, the expres- sion of which in turn is dependent upon stimulation by interleukin-1 and tumor necrosis factor secreted by the T lymphocytes.17 Calcitriol binds to a specific intracellular receptor present in many tissues, particu- larly the bone and intestine. Ligand-receptor interac- tion results in increased intestinal absorption of cal- cium and phosphate from the intestine, and enhanced osteoclastic activity leading to osteolysis and hyper- calcemia. NLPHL is characterized by indolent nodal dis- ease that tends to relapse after standard radiotherapy or chemotherapy. The malignant cells of NLPHL are CD20+ and therefore Rituximab may have activity with fewer late effects than standard therapy. Recent- ly, two phase II studies and a few case reports have been reported on the use and efficacy of Rituximab in patients with NLPHL. In a phase II study reported by Ekstrand et al.,18 22 patients with CD20+ NLPHL received 4 weekly doses of rituximab at 375 mg/m2. Ten patients had previously been treated for Hodgkin’s disease, while 12 patients had untreated disease. All 22 patients responded to Rituximab (overall response rate, 100%) with complete response in 9 (41%), un- confirmed complete response in 1 (5%), and partial response in 12 (54%). Acute treatment-related adverse events were minimal. With a median follow-up of 13 months, 9 patients had relapsed, and the estimated median freedom from progression was 10.2 months. Progressive disease was biopsied in 5 patients: 3 had recurrent NLPHL, while 2 patients had transformed to NHL. All 3 patients with recurrent NLPHL were retreated with Rituximab again. In a second study re- I K R A M A B U R N E Y, V N I R M A L A , M A N S O U R S A L - M O U N D H R I A N D N I C H O L A S J WO O D H O U S E 250 ported by Rehwald et al., 19 14 patients were treated in a manner similar to the one described earlier. How- ever, in this series, all patients had received at least one prior chemotherapy regimen. The overall response was 86%, with 8 complete remissions and 4 partial re- missions, and 2 patients with progressive disease. At a median follow-up of 12 months, 9 of 12 responders were in remission. Our patient was treated with single agent Rituximab, because of poor performance status at presentation, multiple co-morbids including acute renal failure and diabetec neuropathy, and cardiomy- opathy, and perceived poor tolerance to combination chemotherapy. In conclusion, we report the case of an elderly gen- tleman, with multiple co-morbids, who presented with severe hypercalcemia secondary to NLPHL, which to our knowledge has not been reported before, and was successfully treated with anti-CD20 antibody, and is in complete remission more than 3 years after comple- tion of treatment. A C K N OW L E D GE ME N TS We acknowledge with gratitude the help of medical, nursing and the technical staff involved in the care of this patient at Sultan Qaboos University Hospital, Oman. Our special thanks are due to Dr. Omayma El- Shafie and Dr. Azhar Rizvi for the help in the medical management. R E F E R E N C E S 1. Ekstrand BC, Horning SJ. Lymphocyte predominant Hodgkin’s disease. Curr Oncol Rep 2002; 4:424-433. 2. Diehl V, Sextro M, Franklin J Hansmann ML, Harris N, Jaffe E et al. 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